3,4-methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative used recreationally by humans. Despite its illicit status and knowledge that MDMA is highly neurotoxic to brain serotonin systems in animals, reports of human MDMA have increased. The purpose of this project is twofold: 1) to confirm and extend data suggesting that recreational MDMA users incur damage to central serotonin neurons; and 2) to further probe for functional consequences of MDMA GRexposure. In particular, biochemical and fucntional studies will be performed in a controlled inpatient setting to address the following specific questions: 1) Biochemical Studies: a) using CSF measurements of monoamine metabolites, can it be determined: (i) whether MDMA neurotoxicity is dose (exposure) related; (ii) whether there are sex differences in the response to MDMA neurotoxicity; and (iii) whether CSF HVA is also reduced in MDMA users with greatest exposure. b) Using neuroendocrine challenge with m-CPP, can MDMA-induced alterations in brain serotonin innervation be detected (i.e., are prolactin and/or cortisol responses altered?). 2) Functional Studies: a) Do MDMA users have altered mood, anxiety, temperature, or cognitive responses to pharmacological (m-CPP) challenge? b) Can alterations in mood, anxiety, and cognition (behavioral domains that putatively involve serotonin) be detected in MDMA users in response to physicochemical challenge (tryptophan depletion)? c) Are the previously noted alterations of sleep architecture in MDMA users exacerbated following tryptophan depletion, and does m-CPP differentially affect sleep in MDMA users and controls? d) Do MDMA users have an altered response to ischemic or thermal pain, and is their analgesic response to morphine altered? e) Can differences in impulsivity and hostility that were previously observed in MDMA users be confirmed and extended using other research instruments? By addressing these questions, this research will test the hypothesis that MDMA neurotoxicity generalizes to humans, and that toxicity has functional consequences. The long-term goals of this project are to better delineate the public health resks of recreational MDMA use, and to utilize this unique population of individuals to further elucidate the role of brain serotonin in health and disease.